1-aroylalkyl-4-diphenylmethyl piperidines

ABSTRACT

NOVEL COMPOUNDS USEFUL AS ANTIHISTAMINE AGENTS, ANTIALLERGY AGENTS, AND BRONCHODILATORS ARE REPRESENTED BY THE FOLLOWING FORMULA   1-(Z-CO-(CH2)N-),4-((PHENYL)2-C(-R)-),4-R1-PIPERIDINE   WHEREIN R REPRESENTS HYDROGEN OR HYDROXY; R1 REPRESENTS HYDROGEN; OR R AND R1 TAKEN TOGETHER FROM A SECOND BOND BETWEEN THE CARBON ATOMS BEARING R AND R1; N IS A POSITIVE WHOLE INTEGER OF FROM 1 TO 3; Z REPRESENTS THIENYL, PHENYL, OR SUBSTITUTED PHENYL WHEREIN THE SUBSTITUENTS ON THE SUBSTITUTED PHENYL MAY BE ATTACHED AT THE ORTHO, META, OR PARA POSITIONS OF THE PHENYL RING AND ARE SELECTED FROM HALOGEN, A STRAIGHT BRANCHED LOWER ALKYL CHAIN OF FROM 1 TO 4 CARBON ATOMS, A LOWER ALKOXY GROUP OF FROM 1 TO 4 CARBON ATOMS, DI(LOWER) ALKYLAMINO, OR A SATURATED MONOCYCLIC HETEROCYLIC GROUP SUCH AS PYRROLIDINO, PIPERIDINO, MORPHOLINO, OR N-(LOWER) ALKYLPIPERAZINO. PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALTS AND INDIVIDUAL OPTICAL ISOMERS OF COMPOUNDS OF THE ABOVE FORMULA ARE ALSO INCLUDED AS A PART OF THIS INVENTION.

United States Patent 3,806,526 1-AROYLALKYL-4-DIPHENYLMETHYL PIPERIDINES Albert A. Carr, Cincinnati, and C. Richard Kinsolving,

Terrace Park, Ohio, assignors to Richardson-Merrell Inc., New York, NY. 1 No Drawing. Filed Jan. 28, 1972, Ser. No. 221,823

Int. Cl. C07d 29/28 US. Cl. 260-29364 16 Claims ABSTRACT OF THE DISCLOSURE Novel compounds useful as antihistamine agents, antiallergy agents, and bronchodilators are represented by the following formula III 2) r wherein R represents hydrogen or hydroxy; R represents hydrogen; or R and R taken together form a second bond between the carbon atoms bearing R and R n is a positive whole integer of from 1 to 3; Z represents thienyl, phenyl, or substituted phenyl wherein the substituents on the substituted phenyl may be attached at the ortho, meta, or para positions of the phenyl ring and are selected from halogen, a straight or branched lower alkyl chain of from 1 to 4 carbon atoms, a lower alkoxy group of from 1 to 4 carbon atoms, di(lower)alkylamino, or a saturated monocyclic heterocyclic group such as pyrrolidino, piperidino, morpholino, or N-(lower)alky1piperazino. Pharmaceutically acceptable acid addition salts and individual optical isomers of compounds of the above formula are also included as a part of this invention.

FIELD OF INVENTION This invention relates to novel substituted piperidine derivatives. More particularly this invention relates to 4- diphenylmethyl-, 4-(a-hydroxy-a-phenylbenzyl)-, and 4- diphenylmethylenepiperidine derivatives which are useful as antihistamines, antialler'gy agents and bronchodilators and to methods of making and using the same.

SUMMARY OF INVENTION The novel substituted piperidine derivatives of this invention useful as antihistamines, antiallergy agents, and bronchodilators are represented by the formula 2)n- 7-Z Formula I wherein R represents hydrogen or hydroxy; R represents hydrogen; or R and R taken together form a second bond between the carbon atoms bearing R and R n is a positivewhole integer of from 1 to 3; 2' represents thienyl, phenyl or substituted phenyl wherein the substituents on the substituted phenyl are selected from a halogen atom, such as chlorine, fluorine, bromine, or iodine, a straight or branched lower alkyl chain of from 1 to 4 carbon atoms, a lower alkoxy group of from 1 to 4 carbon atoms, a di(lower)alkylamino group, or a saturated monocyclic heterocyclic group such as pyrrolidino, piperidino, morpholino, or N-(lower) alkylpiperazino and may be attached at the ortho, meta, or para positions of the phenyl ring. Included in the scope of this invention are the pharmaceutically acceptable acid addition salts and individual optical isomers of the compounds of Formula I.

DETAILED DESCRIPTION OF INVENTION III 0 (CH1) n -Z Formula II ((-IJHI)I EZ Formula III I (CH2) n 'Z Formula IV In the above Formulas II, III and IV, n and Z have the same meanings defined hereinbefore.

The term lower alkyl as used in describing the compounds of this invention is taken to mean a straight or branched alkyl chain of from 1 to 4 carbon atoms. As examples of lower alkyl groups that may be present in the compounds of Formulas I to IV as a straight or branched lower alkyl substituent, or in the di(lower)a1- kylamine substituent, or in the N-(lower)alkylpiperazine substituent on Z when Z represents a substituted phenyl there may be mentioned, methyl, ethyl, n-propyl, n-butyl, isopropyl, isobutyl and tert-butyl.

The preferred compounds of this invention are those of general Formulas II and III wherein n and Z have the meanings defined hereinbefore. These compounds have superior. antihistamine andantiallergy properties and are bronchodilatorsr In addition thesecompounds are characterized by minimal central nervous system stimulant and depressant efiects, thus making them particularly useful as antihistamines,'antiallergy; agents, and bronchodilators.

The more preferred compounds of this invention are those of general Formula III wherein n is equal to 3, and Z has the meaning defined hereinbefore and are represented by the following general Formula V.

In the above general Formula V, Z has the meaning defined hereinbefore.

, This invention also includes the pharmaceutically acceptable acid addition salts of the compounds of the hereinbefore set forth formulas, optical isomers and salts thereof. Pharmaceutically acceptable acid addition salts of the compounds of this invention are those of any suitable inorganic or organic acid. Suitable inorganic acids are, for example, hydrochloric, hydrobromic, sulphuric, phosphoric acids and the like. Suitable organic acids include carboxylic acids such as, for example, acetic, propionic, glycolic, lactic, pyruvic, malonic, succinic, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, and dihydroxymaleic, benzoic, phenylacetic, 4 aminobenzoic, 4-hydroxybenzoic, anthranilic, cinnamlc, salicylic, 4-aminosalicylic, 2-phenoxybenzoic, 2-acetoxybenzoic, mandelic acid and the like, sulfonic acids such as, for example, methanesulfonic, ethanesulfomc, B-hydroxyethanesulfonic acid, and the like.

As examples of compounds illustrative of th1s invention there may be mentioned, for example,

4'-fluoro-4- (4-diphenylmethylenepiperidino butyrophenone,

3- 4-diphenylmethylenepiperidino 1- (Z-threnyl) l-propanone,

4- (4-diphenylmethylenepiperidino) butyrophenone,

4'-ethyl-4- (4-diphenylmethylenepiperldino butyrophenone,

4-fiuoro-4- [4- a-hydroxy-a-phenylb enzyl piperidino] butyrophenone.

4'-fluoro-3- [4- a-hydroxy-u-phenylbenzyl) piperidino] propiophenone,

4- 4- u-hydroxya-phenylbenzyl piperidino] -4'-p1peridinobutyrophenone,

2- (4-diphenylmethylpiperidino -acetophenone,

4'-ethyl-3- 4- a-hydroxy-a-phenylbenzyl piperidino] propiophenone,

Formula V '4'-di-n-propylamino-4- [4-(a-hydroxy-a-phenylbenzyl) piperidino]butyrophenone, 4'-tert-butyl-4- [4- a-hydroxya-phenylbenzyl piperidino]butyrophenone,

and the like.

As examples of the more preferred compounds of this invention there may be mentioned, for example,

4-ethyl-4- [4- ot-hydroxya-phenylbenzyl) piperidino] butyrophenone, I

4-,[4-(a-hydroxy-u-phenylbenzyl)piperidino] 4'.-piperidinobutyrophenone, j

4'- [4- ('a-hydroxy-a-phenylbenzyl piperidino] -4-dimethylaminobutyrophenone,

4- [4- a-hydroxy-a-phenylbenzyl) piperidino] butyro phenone,

4- [4- (a-hydroxy-a-phenylbenzyl piperidino] -4'-methoxybutyrophenone,

4'-tert-butyl-4- [4- a-hydroxy-a-phenylbenzyl) piperidino]butyrophenone,

4- [4- ot-hydroxy-a-phenylbenzyl piperidino] 1- (2-thienyl)-1-butanone,

4'-fluoro-4- [4- a hydroxy-a-phenylbenzyl piperidino] butyrophenone,

and the like.

The novel compounds of this invention are useful'as antihistamines, antiallergy agents and bronchodilators and may be administered alone or with suitable pharmaceutical carriers, and can be in solid of liquid form such as, for example, tablets, capsules, powders, solutions, suspensions, or emulsions.

The compounds of this invention can be administered orally, parenterally, for example, subcutaneously, intravenously, intramuscularly, intraperitoneally, by intranasal instillation or by application to mucous'membranes such as that of the nose, throat, and bronchial tubes, for example, in an aerosol spray containing small particles of a compound of this invention in a spray or dry powder form. 1

The quantity of novel compounds aoministereu will vary. Depending on the patient and the mode of administration, the quantity of novel compound administered may vary over a wide range to provide in a unit dosage of from about 0.01 to 20 milligrams per kilogram of body weight of the patient per dose to achieve the desired effect. For example the desired antihistamine, antiallergy and bronchodilator effects can be obtained by consumption of a unit dosage form such as, for example, a tablet containing 1 to 50 milligrams of a novel compound of this invention taken 1 to 4 times daily.

The solid unit dosage forms can be of the conventional type. Thus, the solid form can be a capsule which can be of the ordinary gelatin type containing a novel compound of this invention and a carrier, for example, lubricant and inert fillers such as lactose, sucrose, corn starch, and the like. In another embodiment, the novel compounds are tabletted with conventional tablet bases such as lactose, sucrose, corn starch, and the like in combination with binders such as acacia, corn starch or gelatin, disintegrating agents such as corn starch, potato starch, or alginic acid, and a lubricant such as stearic acid, or magnesium stearate.

The novel compounds may also be administered as injectable dosages by solution or suspension of the compounds in a physiologically acceptable diluent with a pharmaceutical carrier which can be a sterile liquid such as water and oils, with or without the addition of a surfactant and other pharmaceutically acceptable adjuvants illustrative of oils there can be mentioned those of petroleum, animal, vegetable or synthetic origin, for example, peanut oil, soybean oil, mineral oil, and the like. In general, water, saline, aqueous dextrose, and related sugar solutions, ethanols and glycols such as propylene glycol or polyethylene glycol are preferred liquid carriers, particularly forinjectable solutions.

For use as aerosols the novel compounds in solution or suspensions may be packaged in a pressurized aerosol container together with a gaseous or liquefied propellant, for example, dichlorodifluoromethane, dichlorodifluoromethane with dichlorodifiuoroethane, carbon dioxide, nitrogen, propane, etc. with usual adjuvants such as cosolvents, and wetting agents, as may be necessary or desirable. The compounds may also be administered in a nonpressurized form such as in a nebulizer or atomizer.

To illustrate the utility of the compounds of this invention the following tabulation indicates the amount of certain representative compounds of this invention required to reduce by 50% wheals induced by intradermal pound was orally administered one hour prior 'to' the histamine injection.

Ex. EDw: No. Compound mgJkg 4"... 4-[4-(a-hydroxy-a-phenylbenzyl)piperidine]- -(2- 3.1

- thienyDbutan-l-one hydrochloride. 5. 444-(a hydroxy-a-phenylbenzyl)-plperidlno]-4'- 1. 9

methylbutyrophenone hydrochloride.

iperidino1butyrophenon hydrochloride. s 4

The minimal amountsof the compound of Examples 4, 5, 6 and 9 requiredto prevent aerosol antigen induced bronchial spasms and, death in the guinea pig are respectively 1.0, 4.0, 1.0 40 milligrams perkilogram of body weight orally. V

The example numbers of-the above mentioned compounds correspond tothe example numbers of the specific examples of compoundsused to illustrate the invention.

The compounds of this invention may be preparedby several methods." Some of the compounds of this invention are used to prepare other compounds of the invention as -will be apparent from the following. The compounds'of Formula I may be prepared by reacting a substituted piperidine, Compound 1, with an w-haloalkyl aryl ketone,-Compou'nd 2, as indicated by the following:'

In the above reaction halo represents a reactive halogen atom, R, R and Z have the meanings defined in Form u'laI. I I I w The abovereaction is carried out in alcoholic solvents such as methanol, ethanol, isopropyl alcohol, n-butanol, and the 'like, in ketone solvents such as methyl isobutyl ketone, and the like, in hydrocarbon solvents'such 'as benzene, toluene, and the like, or in halogenated hydrocarbons, such as chlorobenzene, and the like, in the presence of an inorganicbase suchas'sodi um bicarbonate, potassium carbonate and the like, or in the presence of an organic base such as triethylamine, or an excess of Compound 1. In some cases it may be desirable to add catalytic amounts of potassium iodide to the reaction mixture. The reaction time is usually about 48 hours, but may vary from'about 4 to 120 hours at atemperature of from about 70 C. to the reflux temperature of the solvent. The w-haloalkyl aryl ketone derivatives, Compound2, are commercially available, or maybe prepared by reacting the appropriatew-haloalkanoyl halide andaromatie compounds in the presence of aluminum chloride. They may also be prepared by reacting a substituted phenyl Grignard reagent with w-haloalkanonitriles, followed by the usual work up.

The 4 diphenylmethylpiperidine and 'u,a-diphenyl-4- piperidinemethanol"starting materials as represented by Compoundl wherein R is hydrogen or hydroxy, and R is hydrogen are commercially available. 4-diphenylmethylenepiperidine as represented by Compound 1 wherein R and R form a second bondbetween the carbon atoms bearing R and Rl maybe prepared by dehydration of ot,ot diphenyl-4-piperidine-methanol by generally known procedures.

The compounds of Formula 'I wherein n is the integer 2, may also be'preparedbya MaunichIReaction of a,a-

6 diphenyl-4-piperidinemethanol with a methyl aryl ketone derivative of the formula wherein Z has the meaning defined in Formula I, in the presence of formaldehyde. Suitable solvents for this reaction include acetic acid, methanol, ethanol, n-propanol, nbutanol and the like. The reaction is carried out in the presence of a small amount of mineral acid, such as, for example, concentrated hydrochloric acid for about 3 to 24 hours, generally about 8 hours, at a temperature of from about 50-l00 C.

-The.compounds of Formula I may also be prepared by the reaction of an appropriately substituted l-piperidinealkanonitrile wtih an organometallic compound such as an aryl Grignard or an aryllithium compound in a solvent such as diethyl ether or tetrahydrofuran followed by isolation and purification of the aryl 4-substituted piperidinoalkyl ketone derivative by generally known procedures. The nitrile derivative is obtained by the reaction of an appropriately substituted piperidine compound with an haloalkylnitrile.

The compounds of Formula I wherein Z represents a substituted phenyl wherein the substituents on the substituted phenyl are selected from a di(lower)alkylamino group or a saturated monocyclic heterocyclic group and are attached at the orthoor para-position of the phenyl ring may also be prepared from the corresponding halogen substituted phenyl derivative, preferably a fluoro derivative, using an excess of the dialkylamine or the heterocyclic amine. When volatile amines are employed the amine may be bubbled through a solution of the halogen substituted phenyl derivative in dimethylsulfoxide at about C. for about 4 to 8 hours. When higher boiling amines are employed such as, for example, piperidine, excess amounts of the amine are used as base, reactant, and solvent for the reaction which is carried out at the reflux temperature of the amine for about 4 to 24 hours.

The following specific examples are illustrative of the invention.

EXAMPLE 1 -fluoro-4- [4- a-hydroxy-m-phenylbenzyl piperidine butyrophenone hydrochloride A mixture of 26.73 g. (0.1 mole) of u,a-diphenyl-4- piperidinemethanol, 22 g. (0.11 mole) of 4-chloro-4-fiuorobutyrophenone, a trace of potassium iodide and 13.5 g. (0.16 mole) of sodium bicarbonate in 500 ml. of toluene was refluxed for 2% days. The mixture was filtered, and the filtrate was cooled. The resulting solid was converted by generally known methods to the hydrochloride salt which was recrystallized from methanol and butanone to give the desired product, M.P. 224.5-225.5 C.

EXAMPLE 2 4-fluoro-3-[4-(a-hydroxy-a-phenylbenzyl)piperidino]- propiophenone hydrochloride A mixture of 30.4 g. (0.1 mole) of a,a-diphenyl-4- piperidinemethanol hydrochloride, 9 g. (0.3 mole) of paraformaldehyde and 13.8 g. (0.1 mole) of 4'-fiuoroacetophenone in 100 ml. of isopropyl alcohol containing 2 drops of concentrated HCl was refluxed for 24 hours. The mixture was filtered and the filtrate concentrated to about 100 ml. and cooled. The resulting precipitate was filtered off and recrystallized from ethanol and isopropyl alochol to give the desired product, M.P. 250 C.

EXAMPLE 3 4- [4- (a-hydroxy-u-phenylbenzyl piperidino] butyrophenone hydrochloride To 53.4 g. (0.2 mole) of 01,0: diphenyl-4-piperidinemethanol in 1 liter of toluene was added 38.4 g. (0.21 mole) of 4-chlorobutyrophenone, 21 g. (0.25 mole) of sodium bicarbonate and 0.1 g. of potassium iodide. The mixture was stirred and refluxed for 72 hours then filtered. The filtrate was concentrated to 300 ml. and allowed to stand at room temperature until a precipitate formed. The precipitate was filtered oflf and dissolved in hot toluene, filtered and cooled. A solid formed which was dissolved in diethyl ether and treated with ethereal HCl. The resulting product was recrystallized from methanol-butanone to give the titled compound, M.P. 193.5195 C.

EXAMPLE 4 4- [4- a-hydroxy-a-phenylbenzyl) piperidino] 1- (2- thienyl )-butanl-one hydrochloride A mixture of 53.5 g. (0.2 mole) of a,a-diphenyl-4- piperidinemethanol, 41.5 g. (0.22 mole) of 4-chloro-1-(2- thienyl)-1-butanone, 33.6 g. (0.4 mole) of sodium bicarbonate and a small amount of potassium iodide in 1 liter of toluene was refluxed for 24 hours then filtered. The filtrate was cooled to room temperature, treated with charcoal, and filtered. The solvent was removed under vacuum and 500 ml. of diethyl ether was added to dissolve the residue, followed by treatment with ethereal HCl. The resulting precipitate was recrystallized from methanol-butanone to give the desired product, M.P. 192.5- 193.5 C.

EXAMPLE 5 4- [4- a-hydroxy-a-phenylb enzyl piperidino] -4'-methy1- butyrophenone hydrochloride A mixture of 53.5 g. (0.2 mole) of u,a-diphenyl-4- piperidinemethanol 43.3 g. (0.22 mole) of 4-chloro-4'- methylbutyrophenone, 33.6 g. (0.4 mole) of sodium bicarbonate and a small amount of potassium iodide in 1300 ml. of toluene was refluxed for 17 hours collecting the evolved water in a Dean-Stark trap. The mixture was filtered and the solvent removed. The residue was dissolved in ether and treated with ethereal HCl, and the resulting precipitate was washed with dry ether and recrystallized from ethyl acetate-methanol and from isopropyl alcohol to give the desired product, M.P. 236-237 C.

EXAMPLE 6 4'-tert-butyl-4-[4-(u-hydroxy-a-phenylbenzyl) piperidino]-butyrophenone hydrochloride A mixture of 107 g. (0.4 mole) of u,a-diphenyl-4-piperidinemethanol, 105 g. (0.44 mole) of 4-tert-butyl-4- chlorobutyrophenone, 70 g. (0.7 mole) of potassium bicarbonate, and a small amount of potassium iodide in 600 ml. of toluene was refluxed and stirred for 2 /2 days then filtered. The filtrate was treated with charcoal, filtered through celite then treated with ethereal HCl. The resulting solid was recrystallized from methanol and isopropyl alcohol to give the desired product, M.P. 234-235" C.

EXAMPLE 7 4-bromo-4- [4-(u-hydroxy-u-phenylbenzyhpiperidino] butyrophenone hydrochloride A mixture of 45.4 g. (0.17 mole) of a,a-diphenyl-4- piperidinemethanol, 49.99 g. (0.19 mole) of 4'-bromo-4- chlorobutyrophenone, 3-0 g. (0.3 mole) of potassium bicarbonate and 700 ml. of toluene was refluxed for 3 days. Upon cooling to room temperature the mixture was filtered, and the filtrate was cooled and treated with ethereal HCl then ether. The resulting solid was washed with ether, dried, and dissolved in 2 liters of methanol. The solution was treated with charcoal, filtered, and concentrated to a 500 ml. volume. Isopropyl alcohol was added to the concentrate and heated to a vapor temperature of 73 C. The concentrate was cooled to room temperature, and a product crystallized which was washed with isopropyl alcohol then ether and recrystallized from isopropyl alcohol-water, and isopropyl alcohol to give the title compound, M.P. 251-2525 C.

8 EXAMPLE 8 4'-fluoro-2-[4-(a-hydroxy-u-phenylbenzyl)piperidino] acetophenone hydrochloride hydrate To 40 g. 0.15 mole) of a,a-diphenyl-4-piperidine-methanol in 800 ml. of benzene was added 16.8 g. (0.2 mole) of sodium bicarbonate followed by 27.6 g. (0.16 mole) of 2-chloro-4-fluoroacetophenone in 25 ml. of benzene. The

mixture was stirred and refluxed for 53 hours, filtered, and the filtrate was concentrated to an oil. The oil was dissolved in diethyl ether, washed with water, dried over anhydrous magnesium sulfate, filtered and treated with ethereal HCl. The resulting precipitate was recrystallized from ethanol-water and ethanol-hexane to give the title compound, M.P. 171-174 C., (anhydrous 231-3 C.).

EXAMPLE 9 4- [4- (a-hydroxy-a-phenylbenzyl piperidino] -4'- piperidino-butyrophenone A mixture of 15 g. (0.035 mole) of 4'-fluoro-4-[4-(uhydroxy cc phenylbenzyl)piperidino] butyrophenone, the free bases of the compound of Example 1, and a small amount of potassium iodide in ml. of piperidine was refluxed for 22 hours. The unreacted piperidine was removed under vacuum, and the remaining residue was triturated with water, the water decanted, and the residue dissolved in methanol and added to a large amountof water. The resulting precipitate was dissolved in a large volume of ether, dried over magnesium sulfate, treated with charcoal and filtered. The filtrate was concentrated to a 50 ml. volume and cooled, yielding a product which was recrystallized from ether to give the title compound, M.P. 137.5-139 C.

- EXAMPLE 10 4- (4-diphenylmethylpiperidino butyrophenone hydrochloride v A mixture of 175.5 g. (0.7 mole) of 4-diphenylmethylpiperidine, 63.6 g. (0.35 mole) of 4-chlorobutyrophenone, 600 ml. of toluene, and a small amount of potassium iodide was refluxed for three days then allowed to stand at room temperature one day. The solvent was removed at reduced pressure, and one liter of dry ether was. added after which the mixture was filtered. The filtrate was concentrated, and the residue was dissolved in 75-90 petroleum ether treated with charcoal and filtered. The filtrate was cooled to room temperature and. the resulting precipitate was filtered olf, and dissolved in ether then treated with ethereal HCI. A precipitate formed which was recrystallized from' methanol-butanone to give the desired product, M.P. 163.5-164.5 C.

EXAMPLE 11 A mixture of 125.5 g. (0.5 mole) of 4-diphenylmethylpiperidine, g. (0.55 mole) of 4-fluoro-4-chlorobutyrophenone, 110 g. (0.8 mole) of potassium carbonate, a small amount of potassium iodide and 600 ml. of methyl isobutyl ketone was refluxed and stirred for 2 /2 days, then filtered. The filtrate was concentrated under reduced pressure. The remaining residue was dissolved in ether and treated with ethereal HCl. A gummy residue formed which was dissolved in ethyl acetate with a small amount of water and heated on a steam bath to a vapor temperature of 77 C. then cooled. The resulting precipitate was washed with ether and recrystallized from ethyl acetate, toluene and isopropyl alcohol to give the desired product, M.P. 194-195.5 C.

EXAMPLE 12 4-dimethylamino-4- [4- (u-hydroxy-a-phenylb enzyl) piperidino]-butyrophenone Through a solution of 18 g. (0.041 mole) of 4'-fluoro- 4 [4 (a hydroxy-a-phenylbenzyl)piperidino]butyro- 9 phenone in '150. ml. of dimethylsulfoxide,.(DMSQiwas vigorously bubbled. dimethyl-amine for 6 hon 1.00 C. Mostof the-DMSO- was removedat-reduc pressure and a temperature of 120 C. The remaining nuxturewas poured into water and sodium carbonate tojwhichwas added a small amount .of methanol. The resulting solid was filtered and dissolved in warm methanol and isopropyl alcohol, treated with charcoal; filtered, and cooled.'-Th'e solid which formed upon cooling-"was filteredoff and re crystallized from 'acetone-heptarie uct, M.P. 148-150" C.

EXAMPLE 13f I By the procedure of Example 1:1 on'ly s'ubstituting' for 4'-flu0ro-4-chlorobutyrophenone an appropriate amount of 4-chloro-4'-ethylbutyrophenone or 4-chloro-4f'jethoxybutyrophenone the following compounds are obtained;

4-(4-diphenylmethylpiperidino)-4-ethylbutyrophenone hydrochloride, T 4- (4-diphenylmethylpiperidino -4'-ethoxybutyrophenone hydrochloride. q

EXAMPLE 14 EXAMPLE 1s 4-flu0ro-4- (4-diphenylmethylenepiperidino) butyro phenone A mixture of 99.9 g. (0.4 mole) of 4-diphenylmethyl enepiperidine, 88 g. (0.44 mole) of 4-chloro-4'-fluorobutyrophenone, 64.0 g. (0.64 mole) of potassiumbicarbomate and a small amount of potassium iodide in" 1500 ml. of toluene was refluxed for days. The reactionture was filtered, and the filtrate was concentrated at reduced pressure leaving a residue which was dissolved in about 800 ml. of ethyl acetate. This solution was concentrated to about 500 ml. and allowed to stand for one day. The resulting precipitate was recrystallized from methanolethyl acetate, made basic with sodium hydroxide solution, water washed, and the product recrystallized from 7590 petroleum ether to give the title compound, M.P. 111- EXAMPLE 16 An illustrative composition for hard gelatin capsules is as follows:

The formulation is prepared by passing the dry powders of (a) and (b) through a fine mesh screen and mixing them well. The powder is then filled into hard gelatin capsules at a net fill of 115 mg. per capsule.

to give the desired rod:

EXAMPLE 17 Ari illustrativecomposition for tablet is as follows: Mg.

compound (a) and part of the starch and granulated with starch paste is dried, screened, and mixed with the magnesium stearate. The mixture is compressed into tablets weighing 110 mg; each. L

'" EXAMPLE 18 An illustrative composition for an aerosol solution is the following:

L Weight percent (a) 4-[4-(a-hydroxy a phenyl-benzyl)piperidino] The materials (a), (b) and (c) are packaged in ml.

stainless steel containers equipped with a metering valve designed to meter 0.2 gram per dose, an equivalent of 10 mg. of novel compound (a).

EXAMPLE 19 An illustrative composition for an aerosol suspension is the following:

' Weight percent (a)"4-[4-'(q-hydroxy a phenylbenzyl)piperidino] ""butyrophe'rione (particle size 1Qu.) 20.0 (5')"sorbi'tanitrioleate 0.5 (c) Diehlorodifluoromethane 39.75 (d) D'ichlorodifluoroethane 39.75

Thematerials (a)-(d) arepackaged in 15 ml. stainless steel containers equipped with a metering valve designed to;meter. 50 mg. per dose, an equivalent of 10 mg. of novel compound.(a).

-'-.' EXAMPLE 20.

An illustrative composition for an injectable suspension isthetollowing. 1 mluampul for an intramuscular in- JCCHOH. Weight percent (a) .4 [4-(ughydroxy-a phenylbenzyl)piperidino] 4'- me thoxybutyrophenone, hydrochloride (parti;

cle si 0#) --,.-1- b) Polyvinylpyrrolidone (M.W. 25000) 0.5 (c) Lecithin 0.25 (d) Water for injection to make 100.0

The materials (a)-(d) are mixed, homogenized, and filled into 1 ml. ampuls which are sealed and autoclaved 20 minutes at 121 C. Each ampul contains 10 mg. per ml. of novel compound (a).

EXAMPLE 21 4'-dimethylamino-2- 4-diphenylmethylpiperidino aceto phenone mono-hydrochloride Through a solution of 20 g. (0.0515 mole) 2-(4-diphenylmethylpiperidino)-4-fluoroacetophenone in ml. of dimethylsulfoxide (DMSO) was bubbled dimethylamine for 6 hours at 100" 0. Most of the DMSO" was evaporated at reduced pressure, and the remaining mixture was added to water and sodium bicarbonate. The precipitate was removed and converted to the acid hydrochloride which recrystallized from ethyl acetate or butanol or ethanol-ethyl acetate to give the title compound,

2612-5" C. (Free base of title compound, M.P. 107- 1 1 EXAMPLE 22 4-ethyl-4- [4- a-hydroxy-a-phenylbenzyl )piperidino] butyrophenone hydrochloride By the procedure of Example 6 only substituting for 4'- tert-butyl-4-chlorobutyrophenone, an appropriate amount of 4-ethyl-4-chlorobutyrophenone, the desired product is obtained. v

EXAMPLE 23 a 4- [4 (oz-hydroxy a-phenylbenzyl) pipidino] 4f -m ethoxybutyrophenone hydrochloride 7 By the procedure of Example 6, only substituting for 4' tert butyl 4 chlorobutyrophenone an appropriate amount of 4'-methoxy-4-chlorobutyrophenone, and refluxing the mixture for 48 hours the desired product was obtained upon recrystallization from methanol-butanone, M.-P. 219-221 C. e

We claim:

v 1. A compound selected from a base of the formula I M x T)n wherein R is selected from the group consisting of hydrogen or hydroxy; n is a positive integer of from 1 to 3; and Z is selected from the group consisting of thienyl, phenyl, or substituted phenyl wherein the substituents on the substituted phenyl may be attached at the ortho, meta, or para positions of the substituted phenyl ring and'are selected from the group consisting of a halogen atom, a straight or branched alkyl chain of from 1 to 4 carbon atoms, a lower alkoxy group of from 1 to 4 carbon atoms, i

a di(lower)alkylamino group, or a saturated monocyclic heterocyclic ring selected from the group'consisting of pyrrolidino, piperidino, morpholino, and N-(lower)alkylpiperazino; and pharmaceutically acceptable acid addition salts thereof. 1 I

2.' A compound of claim 1 wherein R represents-by 5. A compound of claim 4 which is 4'-tert-butyl-4-[4- (a-hydroxy-a-phenylbenzyl)piperidino]butyrophenone or a pharmaceutically acceptable acid addition salt thereof. 6. A compound of claim 4 which is 4- [4-(a-hydroxy-aphenylbenzyl)piperidino]-4-methoxybutyrophenone or a pharmaceutically acceptable acid addition salt thereof.

7. A compound of claim 4 which is 4- [4-(a-hydroxy-aphenylbenzyl)piperidino]-1-(2-thienyl)-1-butanone or a pharmaceutically acceptable acid addition salt thereof.

8. A compound of claim 4 which is 4- [4-(a-hydroxy-uphenylbenzyl)piperidino]-4'-piperidinobutyrophenone or a pharmaceutically acceptable acid addition salt thereof.

9. A compound of claim 4 which is 4- [4-(ot-hYd1OXY-ccphenylbenzyl)piperidino]butyrophenone or a pharmaceutically acceptable acid addition salt thereof.

10. A compound of claim 4 which is 4-fiuoro-4- [4-(0chydroxy-a-phenylbenzyl)piperidino]butyrophenone or a pharmaceutically acceptable acid addition salt thereof.

11. A compound of claim 4 which is 4'-dimethylarnino- 4 [4 (a hydroxy-wphenylbenzyl)piperidino] butyrophenone or a pharmaceutically acceptable acid addition salt thereof.

12. A compound of claim 1 wherein R represents hydrogen.

13. A compound of claim 12 which is 4'-dimethylamino-2-(4-diphenylmethylpiperidino)acetophenone or a References Cited UNITED STATES PATENTS Janssen 260-29368 3,097,209 7/1963 Janssen 260-29368 3,122,555 2/1964 Janssen 260-29368 2,739,968 3/1956 Sperber et aL: 260293.8 3,068,237 12/ 1962 Rorig "260-293.84

S. WINTERS, Assistant Examiner JOHN D. RANDOLPH, Primary Examiner US. Cl. X.R.

26 0247.5 .R, 268 PH, 293.68, 293.71, 293.79, 293.8, 293.72, 293.84, 326.5 B, 293.86, 247.2 A, 268 C; 424 

